Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site
Tom G. Caniels, Max Medina-Ramìrez, Shiyu Zhang, Sven Kratochvil, Yuejiao Xian, Ja-Hyun Koo, Ronald Derking, Jakob Samsel, Jelle van Schooten, Simone Pecetta, Edward Lamperti, Meng Yuan, María Ríos Carrasco, Iván del Moral Sánchez, Joel D. Allen, Joey H. Bouhuijs, Anila Yasmeen, Thomas J. Ketas, Jonne L. Snitselaar, Tom P. L. Bijl, Isabel Cuella Martin, Jonathan L. Torres, Albert Cupo, Lisa Shirreff, Kenneth Rogers, Rosemarie D. Mason, Mario Roederer, Kelli M. Greene, Hongmei Gao, Catarina Mendes Silva, Isabel J. L. Baken, Ming Tian, Frederick W. Alt, Bali Pulendran, Michael S. Seaman, Max Crispin, Marit J. van Gils, David C. Montefiori, Adrian B. McDermott, François J. Villinger, Richard A. Koup, John P. Moore, Per Johan Klasse, Gabriel Ozorowski, Facundo D. Batista, Ian A. Wilson, Andrew B. Ward, Rogier W. SandersEliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)–specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.